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An Investigation Into The Genetic Basis of Late-Onset Psoriasis

Hebert, Harry

[Thesis]. Manchester, UK: The University of Manchester; 2015.

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Abstract

Background: Psoriasis is a complex disease with a genetic component contributing to disease pathogenesis. Chronic plaque psoriasis can be dichotomised into two subtypes according to age of onset; type 1 (early-onset; <40 years) and type 2 (late-onset; ≥40 years). Despite clinical and biological differences between the two subtypes, the genetics underpinning late-onset psoriasis remains poorly characterised compared to early-onset psoriasis. Aims: The aim of this project was to identify genetic loci associated with late-onset psoriasis, to assess the overlap of loci with early-onset psoriasis and to elucidate the functional role of the identified variants.Methods: The study had three parts; the first was a candidate-gene association study of the IL1B gene. A total of 16 SNPs from the region were genotyped in 595 late-onset and 1,137 early-onset psoriasis samples and compared to 4,770 controls from the European population. The second was a large-scale study conducted in 543 late-onset psoriasis and 4,373 controls using the Immunochip array. The third was a functional study using bioinformatics data mining, chromatin immunoprecipitation and electrophoretic mobility shift assay techniques to analyse the role of a disease-associated variant at the biological level. Results: The candidate-gene study replicated a previously reported association at a promoter polymorphism, rs16944 (P<0.05), within the IL1B gene and discovered a novel association at a second variant, rs11687624 (P<3.12x10-3), in late-onset psoriasis. None of the variants analysed were significantly associated with early-onset psoriasis. Bioinformatic eQTL data suggests the two variants and their proxies are associated with the expression of IL1A, IL1B, IL38 and PAX8. The Immunochip study identified 6 non-HLA loci (P<2.3x10-5) previously associated with early-onset psoriasis to also be associated with late-onset psoriasis (IFIH1, IL12B, IL23A, IL23R, TRAF3IP2 and ZNF313). Conditional analysis of the MHC region also identified two loci (HLA-C and HLA-A). A novel locus, IL1R1, was associated with late-onset psoriasis, but not early-onset psoriasis. Bioinformatic data mining found no role for the IL1R1 variants as eQTLs and prioritised the IL1B variant rs2708914 for functional analysis. The transcription factor STAT3 was found to be enriched at rs2708914 in keratinocyte and CD8+ T-lymphocyte cell lines. Allele-specific binding could not be established.Conclusions: This project is the largest genetic study of late-onset psoriasis to date and provides evidence that it shares susceptibility loci with early-onset psoriasis as well as having specific susceptibility loci. These findings provide further evidence for the dichotomisation of chronic plaque psoriasis, firstly to facilitate better understanding of the pathogenesis of the two subtypes and secondly to enable tailored therapy to be developed. Both have potential benefits for patients in the future. The genetic and functional studies conducted have provided a platform from which further studies can be carried out.